Process for the preparation of alkyl n-alkylanthranilate

ABSTRACT

This invention is directed to a process of preparing alkyl N-alkylanthranilate, specially Methyl N-methylanthranilate, represented by Formula (I), in a one pot synthesis, using available and cheap commercial chemicals such as Isatoic anhydride, solid sodium hydroxide, dimethyl sulfate and methanol. Purity of the crude product is about 97% and yield 85%.

TECHNICAL FIELD OF THE INVENTION

The invention relates to a process for the preparation of alkylN-alkylanthranilate of the Formula 1.

More particularly it is concerned with the preparation of MethylN-methylanthranilate, Formula 1, R₁═R₂═Me.

BACKGROUND OF THE INVENTION

Methyl N-methylanthranilate (DMA) is a valuable compound used in theflavouring and fragrance industry and is also reported to be a birdrepellent described in patent U.S. Pat. No. 2,967,128.

Several methods are known for the preparation of DMA.

A classical route is N-methylation of methyl anthranilate with amethylating agent as dimethyl sulfate or methyl iodide, cited in patentDE 3936229. To avoid dimethylation, reductive methylation withformaldehyde and hydrogen has been described in patent U.S. Pat. No.4,633,009. Reaction scheme 1.

To prepare methyl anthranilate, 2H-3,1-benzoxazine-2,4(1H)-dione(isatoic anhydride) is reacted under alkaline conditions

with methanol as disclosed in patent IN 146359. Reaction scheme 2.

As disclosed by Staiger, J. Org. Chem. (1959), 24, 1214-19,N-methylisatoic anhydride reacts with methanol under alkaline conditionsto produce Methyl N-methylanthranilate.

Hardtmann, J. Heterocycl. Chem. (1975), 12 (3), 565-72 preparesN-substituted isatoic anhydride by reacting the N-sodium salt of isatoicanhydride, prepared from sodium hydride, with alkyl halides. TheN-benzyl derivative of isatoic anhydride is prepared using potassiumcarbonate and benzyl chloride.

DISCLOSURE OF INVENTION

It is an object of this invention to provide a facile process for thepreparation of N-alkyl alkylanthranilates, specially N-methyl methylanthranilate, in commercial quantities, good yield and high purity.

An obvious route would be a one pot synthesis starting with the readyavailable isatoic anhydride, N-alkylation and final reaction with analcohol to furnish the title product.

Surprisingly it turned out that a solid metal hydroxide or basic metaloxide, preferable sodium or potassium hydroxide in a suitable polarsolvent such as dimethylforamide or 1-methyl-2-pyrrolidinone could formthe N-metal salt with isatoic anhydride.

Depending on solvent, concentration or temperature the metal salt wouldseparate to form a dispersion.

One would anticipate that water formed during the salt formationimmediately would react with isatoic anhydride, forming anthranilicacid.

Surprisingly this was not the case.

Trials using metal alkoxides resulted in that the alkohols formed,reacted with isatoic anhydride to form alkyl esters of anthranilic acid.

N-methylation could be achieved by adding an alkylation agent.Preferably methyl iodide or dimethyl sulfate in a molar ratio, relativeto isatoic anhydride, from 1 to 5, preferably 1.5, at a temperature from10-40° C. In the case of a methylating agent, the intermediateN-methylisatoic anhydride could be isolated by filtration as acolourless crystalline compound by adding 2 parts of water to thereaction mixture. Identification was established by compare HPLCchromatograms with authentic material (supplied by Aldrich).

After N-alkylation of isatoic anhydride has been performed 1 to 50 moleparts of an alkyl alkohol, relative to isatoic anhydride, is added tothe reaction mixture at a temperature between 10 and 40° C. Thetemperature is elevated to distil excess of alkyl alcohol off. Leaving50% to 0% of the alcohol in the reaction mixture. Preferably 10%.

By alcohol addition under alkaline conditions, N-alkylisatoic anhydride,is ring opened, forming alkyl N-alkylanthranilate with subsequentelimination of carbon dioxide.

Alkyl N-alkylanthranilate is isolated by adding 1 to 5 parts of water tothe reaction mixture, and extract the mixture with a non water miscibleorganic solvent.

The extraction solvent could be an alicyclic or cyclic hydrocarbon,halogenated derivatives hereof, aliphatic ethers or esters. Preferablyhexane.

The organic phase is washed with water, and evaporated in vacuo, leavingalkyl N-alkylanthranilate as an oil with purity about 97% and yieldabout 85%.

EXAMPLES

Products were analysed by gas chromatography. Using SRI Instrumentsmodel 310 equipped with column Restek, MXT-5, 15 m, 0.54 ID, FIDdetector and temperature gradient 90-200° C., 10°/min.

Peaks were identified by running authentic samples.

Example 1 Methyl N-methylanthranilate

To dry Dimethylforamide (DMF), 300 mL, covered with nitrogene, solidpulverised sodium hydroxide, 97% assay, 14.12 g, 0.3424 moles, is added.

Isatoic anhydride, 96% assay, 40.00 g, 0.2354 moles, is dissolved in dryDMF, 100 mL.

To the stirred suspension of sodium hydroxide covered with nitrogen, thesolution of isatoic anhydride is added at 30° C. over 30 min. and themixture is stirred for a further 15 min.

Dimethyl sulfate, 32.88 g, 0.2588 moles is added drop wise with stirringover 20 min., allowing temperature to rise to max 45° C. The solution isstirred at ambient temperature for a further 30 min.

Methanol, 50 mL, is added, the mixture is stirred for 15 min at 25° C.Temperature is elevated to distil methanol off. When temperature reaches100° C., the mixture is cooled to 20° C. and water, 800 mL is added.Ammonia solution, 2 mL, 25 w/w % is added to destroy excess dimethylsulfate. P The cloudy mixture is extracted with hexane, 200 mL. Thehexane phase is separated, washed with water and distilled on a rotaryevaporator at 15 mm Hg and 100° C. leaving crude MethylN-methylanthranilate, 33.80 g, with a composition, by GC, of 2.1% Methylanthranilate and 97.5% Methyl N-methylanthranilate, corresponding to ayield of the theoretical of 85%.

Crude Methyl N-methylanthranilate, 33.80 g, is distilled through a 30 cmVigreux column at 130-131° C. at 15 mm Hg, giving 28.10 g MethylN-methylanthranilate with a composition, by GC, of 1.5% Methylanthranilate and 98.5% Methyl N-methylanthranilate.

Example 2

To dry Dimethylforamide (DMF), 75 mL, covered with nitrogene, solidpulverised potassium hydroxyde, 85% assay with 15% water, 5.80 g, 0.0879moles, is added. Isatoic anhydride, 96% purity, 10.00 g, 0.0588 moles,is dissolved in dry DMF, 35 mL.

To the stirred suspension of potassium hydroxide covered with nitrogen,the solution of isatoic anhydride is added at 30° C. over 30 min. andthe mixture is stirred for a further 15 min.

Methyl iodide, 12.50 g, 0.0883 moles is added drop wise with stirringover 20 min., allowing temperature to rise to max 40° C. The solution isstirred at ambient temperature for a further 30 min.

Methanol, 50 mL, is added, the mixture is stirred for 15 min at 25° C.

Temperature is risen so methanol is distilled off. When temperaturereaches 100° C., the mixture is cooled to 20° C. and water, 200 mL isadded, and the mixture is extracted with 2 times hexane. The combinedhexane phases are washed with water and distilled on a rotary evaporatorat 15 mm Hg and 100° C. leaving crude Methyl N-methylanthranilate, 8.10g, with a composition, by GC, of 4.4% Methyl anthranilate and 95.3%Methyl N-methylanthranilate, corresponding to a yield of the theoreticalof 80%.

1. A process for the preparation of an alkyl ester of N-alkylanthranilic acid represented by Formula 1:

wherein R₁ and R₂ independent represent alkyl groups, by reacting2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride) in a polar aproticorganic solvent as medium, with a solid metal hydroxide or basic metaloxide, adding an alkylating agent to form an N-alkyl intermediate andthereafter reacting the intermediate with an alkyl alcohol to form areaction mixture containing the product of Formula
 1. 2. A processaccording to claim 1, wherein the product according to Formula 1 isisolated by adding water to the reaction mixture and is extracted with anon-water miscible apolar organic extraction solvent.
 3. A processaccording to claim 1, wherein said polar solvent is selected from thegroup consisting of a carboxamide, a nitrile, an ether, a sulphoxide andhexaalkyl phosphoric triamide.
 4. A process according to claim 1,wherein said solid metal hydroxide or basic metal oxide is selected fromthe group consisting of hydroxides and oxides of Li, Na, K, Ca and Ba.5. A process according to claim 1, wherein said alkylating agent isselected from alkyl halides, wherein the alkyl group has from 1 to 8carbon atoms and wherein the halide is selected from the groupconsisting of Cl, Br and I.
 6. A process according to claim 1, whereinsaid alkylating agent is selected from dialkyl esters of sulfuric acid(dialkyl sulfates), wherein the alkyl groups have from 1 to 8 carbonatoms and is selected from the group consisting of non-substituted alkylgroups.
 7. A process according to claim 1, wherein said alkyl alcohol isselected from the group consisting of primary, secondary, and tertiaryalcohols all with a maximum of 8 carbon atoms.
 8. A process according toclaim 2, wherein said extraction solvent is selected from the groupconsisting of C⁵⁻¹⁰ linear, branched and cyclic alkanes.
 9. A processaccording to claim 2, wherein said extraction solvent is hexane.
 10. Aprocess according to claim 1, wherein said polar solvent is selectedfrom the group consisting of dimethyl formamide and1-methyl-2-pyrrolidinone.
 11. A process according to claim 1, whereinsaid solid metal hydroxide or basic metal oxide is selected from thegroup consisting of sodium hydroxide and potassium hydroxide.
 12. Aprocess according to claim 1, wherein said alkylating agent is dimethylsulfate.
 13. A process according to claim 1, wherein said alkyl alcoholis methanol.
 14. A process according to claim 1, wherein R₁ and R₂ areeach a methyl group.